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CANCER STEM CELLS AND
ONCOLOGY RESEARCH
11
th
International Conference on
Journal of Medical Oncology and Therapeutics
|
Volume 3
microRNA-17 IS
DOWNREGULATED
IN ESOPHAGEAL
ADENOCARCINOMA
CANCER STEM-LIKE
CELLS AND PROMOTES
A RADIORESISTANT
PHENOTYPE
Stephen G Maher
1
,Niamh Lynam-Lennon
1
, Susan
Heavey
1
, Gary Sommerville
1
, Becky A.S. Bibby
2
,
Brendan Ffrench
3
, Jennifer Quinn
1
, Michael F
Gallagher
3
and
John V Reynolds
1
1
Trinity Translational Medicine Institute, Ireland
2
University of Hull, United Kingdom
E
sophageal adenocarcinoma (EAC) is an aggressive
disease with an extremely poor prognosis. Resistance
to neoadjuvant chemoradiation therapy (CRT) remains a
critical barrier to the effective treatment of EAC. Cancer
stem-like cells (CSC) are a distinct subpopulation of cells
implicated in the resistance of tumors to anti-cancer
therapy. However, their role in the resistance of EAC to
CRT is largely unknown. In this study, using a novel
in vitro
isogenic model of radioresistant EAC, we demonstrate that
radioresistant EAC cells have enhanced tumorigenicity
in
vivo
, increased expression of CSC-associated markers and
enhanced holoclone forming ability. Further investigation
identified a subpopulation of CSC that are characterised
by high aldehyde dehydrogenase (ALDH) activity, enhanced
radioresistance and significantly altered microRNA (miR)
expression alterations, including decreased expression of
miR-17.
In vitro
, miR-17 overexpression was demonstrated
to significantly sensitise radioresistant cells to X-ray
radiation and promoted the downregulation of genes with
miR-17 binding sites, such as C6orf120.
In vivo
, miR-17 was
significantly decreased, whilst C6orf120 was significantly
increased, in pre-treatment EAC tumour samples from
J Med Oncl Ther 2018, Volume 3
patients who demonstrated a poor response to neoadjuvant
CRT. This study sheds novel insights into the role of CSC in the
resistance of EAC to CRT and highlights miR-17 as a potential
biomarker of CRT sensitivity and novel therapeutic target in
treatment resistant EAC.
Maherst@tcd.ie